DGAT2

Official Full Name

diacylglycerol O-acyltransferase 2

Organism

Homo sapiens

GeneID

84649

Background

This gene encodes one of two enzymes which catalyzes the final reaction in the synthesis of triglycerides in which diacylglycerol is covalently bound to long chain fatty acyl-CoAs. The encoded protein catalyzes this reaction at low concentrations of magnesium chloride while the other enzyme has high activity at high concentrations of magnesium chloride. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

Synonyms

ARAT; HMFN1045; GS1999FULL;

Bio Chemical Class

mRNA target

Protein Sequence

MKTLIAAYSGVLRGERQAEADRSQRSHGGPALSREGSGRWGTGSSILSALQDLFSVTWLNRSKVEKQLQVISVLQWVLSFLVLGVACSAILMYIFCTDCWLIAVLYFTWLVFDWNTPKKGGRRSQWVRNWAVWRYFRDYFPIQLVKTHNLLTTRNYIFGYHPHGIMGLGAFCNFSTEATEVSKKFPGIRPYLATLAGNFRMPVLREYLMSGGICPVSRDTIDYLLSKNGSGNAIIIVVGGAAESLSSMPGKNAVTLRNRKGFVKLALRHGADLVPIYSFGENEVYKQVIFEEGSWGRWVQKKFQKYIGFAPCIFHGRGLFSSDTWGLVPYSKPITTVVGEPITIPKLEHPTQQDIDLYHTMYMEALVKLFDKHKTKFGLPETEVLEVN

Open

Disease

Non-alcoholic fatty liver disease

Approved Drug

1 +

Clinical Trial Drug

4 +

Discontinued Drug

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Detailed Information

DGAT2 is the critical catalyzing enzyme for triglyceride biosynthesis. Diacylglycerol acyltransferases (DGATs) play a crucial role in the biosynthesis of triacylglycerol (TG), which is the main storage form of metabolic energy in eukaryotic organisms. Although DGAT2, one of the two different DGATs, plays an important role in TG biosynthesis, little is known about the regulation of DGAT2 activity. Two different diacylglycerol acyltransferases (DGAT) - DGAT1 and DGAT2 - are involved in catalysing the final step of TG biosynthesis by forming a covalent bond between acyl CoA and diacylglycerol (DG). They are both primarily localized in the endoplasmic reticulum (ER), but DGAT2 is also associated with mitochondria and lipid droplets. DGAT2 is highly expressed in liver and adipose tissue and uses nascent DG and de-synthesised fatty acids as substrates to mediate another pathway called glycerophosphate.

Role of DGAT2 in Lipid Metabolism

Dietary lipids are absorbed into the intestinal epithelium as fatty acids and converted to triglycerides by diacylglycerol acyltransferase (DGAT), which are then packaged in celiac particles or stored in cytoplasmic lipid droplets (LDs). Patients deficient in DGAT1 experience vomiting, diarrhoea and protein-losing enteropathy, illustrating the importance of this process to intestinal homeostasis. DGAT1 deficiency leads to reduced LD formation in the intestinal organ tissues of patients and resistance to unsaturated fatty acid lipotoxicity. However, LD formation is not completely lost in patient-derived organ tissues, suggesting an alternative mechanism for LD formation. An unexpected role of DGAT2 in lipid metabolism is suggested, as DGAT2 partially compensates for LD formation and lipotoxicity in DGAT1-deficient intestinal stem cells. Furthermore, (un)saturated fatty acid-induced lipotoxicity is mediated by ER stress. More importantly, overexpression of DGAT2 fully compensated for DGAT1 deficiency in organ tissues, suggesting that induction of DGAT2 expression in patient cells could serve as a future therapeutic target.

Role of DGAT1 And DGAT2 in The Gut

Effects of DGAT1 and DGAT2-mediated lipid metabolism on intestinal epithelial cell homeostasis. Epithelial stem cells express both functional DGAT1 and DGAT2, although DGAT2 was previously expressed only at very low levels in the human intestine. Furthermore, functional expression of DGAT2 is lost upon differentiation towards the enterocyte phenotype and that DGAT2 partially compensates for LD formation and resistance to lipotoxicity when DGAT1 function is inhibited in intestinal stem cells. DGAT1-dependent OA-induced LD formation is tolerated in the absence of DGAT1, which is also partially dependent on DGAT2. In addition, the protective effect of LD is linked to an attenuation of the lipid-induced ER stress response. Finally, overexpression of DGAT2 completely attenuated OA-mediated lipotoxicity in patient-derived DGAT1-deficient enterocytes.

Role of Cysteine And Its Oxidation in Human DGAT2 Enzyme Activity In Vitro

Thiol-modifying reagents (NEM and IA) as well as ROS-related chemicals (H2O2 and β-lapachone) severely inhibit human DGAT2 activity, whereas human DGAT1 and GPAT1 are virtually unaffected. In particular, ROS-related chemicals simultaneously induced intermolecular disulfide cross-linking in human DGAT2. After treatment with the disulfide bond reducer DTT, the oxidative inactivation and disulfide cross-linking were almost completely reversed, suggesting that ROS-induced intermolecular cross-linking plays an important role in the inactivation of human DGAT2 and that DGAT2 is a redox-sensitive regulator of TG biosynthesis.

References:

van Rijn JM, van Hoesel M, de Heus C, et al. DGAT2 partially compensates for lipid-induced ER stress in human DGAT1-deficient intestinal stem cells [published correction appears in J Lipid Res. 2021;62:100126]. J Lipid Res. 2019;60(10):1787-1800. doi:10.1194/jlr.M094201
Jung S, Choi M, Choi K, et al. Inactivation of human DGAT2 by oxidative stress on cysteine residues. PLoS One. 2017;12(7):e0181076. Published 2017 Jul 11. doi:10.1371/journal.pone.0181076

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